Cataract surgery restores sight and is one of the most common surgeries performed. For these reasons, the effectiveness, safety, cost, and accessibility of cataract surgery procedures and therapies are highly significant. Because the evidence base for infection prophylaxis is limited, surgeon practices are highly variable. We propose to conduct a retrospective comparative effectiveness study that will leverage variation in practice among the 297 cataract surgeons providing care to 6.6 million California members of Kaiser Permanente. The study will examine whether the variation in prophylaxis evident among Kaiser Permanente surgeons resulted in differences in infection risk. Recent preliminary data indicate that 71% of surgeons routinely use patient- instilled eye drops before the day of surgery, 26% nurse-instilled eye drops in the pre-op holding area, 13% subconjunctival injection, 30% intracameral injection, and 58% intra-operative eye drops. Nearly all use post- operative eye drops, but there is variation in choice of agent. The study will use these variations to estimate the comparative and incremental effectiveness of prophylactic strategies. The study will use data recorded into the electronic medical record from 460,000 cataract surgeries performed during 2005-2011, of which 350 infections occurred. We will validate the endophthalmitis diagnosis and surgical complications for 1000 patients (all 350 endophthalmitis cases plus a random sample of 700 non- cases). The study will use instrumental variables to make valid inferences, and each prophylactic procedure will be evaluated individually, while holding constant other prophylactic procedures. The rapid, low-cost study we propose is an essential step to developing the knowledge base for future research. We will use the data to fully articulate the rationale for a randomized controlled trial, including information gaps, priorities, and feasibility, and to build surgeon and pharmacist support. In addition, we will elucidate design trade-offs linked to the unit of randomization and consent process, eligibility and population subsets, the number of study arms, contrasts, the measurement system, protocol adherence, and study power. In addition, the comparative-effectiveness study has a high likelihood of immediately informing clinical decision-making on several key issues, most particularly, prophylaxis before the day of therapy, before any surgical complication could occur. If the level of practice variation in the Medicare fee-for-service program mirrors Kaiser Permanente's, then the excess number of infections could be as large as 2,000 annually. If the study demonstrates that pre-operative antibiotic administrations can be eliminated, we calculate potential savings of ~$70 per case in drug costs alone, totaling $127 million annual savings to Medicare. If it further demonstrates that intra- and post- operative administrations can be switched to the older-generation antibiotics, additional savings would amount to ~$60 per case for a total annual savings to Medicare of $236 million annually.